Work‐related dysphonia in subjects with occupational asthma is associated with neutrophilic airway inflammation

To the editor, Vertigan et al. recently highlighted the comorbid association between asthma and laryngeal dysfunction, although the pathophysiological mechanisms underlying this complex association remain largely uncertain. It is widely acknowledged that laryngeal dysfunction, including vocal cord dysfunction, can be triggered by external stimuli, such exercise, strong odors and irritant exposures. In this regard, workplace exposure to respiratory irritants has been reported as an important cause of the “work‐related irritable larynx syndrome”. We sought to assess the clinical characteristics and airway inflammatory processes associated with work‐related dysphonia in a cohort of subjects with sensitizer‐induced occupational asthma (OA) ascertained by a positive specific inhalation challenge (SIC). This retrospective study included 341 subjects identified among the multicenter European network for the PHenotyping of OCcupational ASthma (E‐PHOCAS) who met the following eligibility criteria: (1) complete information on variables addressing asthma severity and control while exposed at work; (2) available information on self‐ reported dysphonia (i.e. hoarseness or loss of voice) at work; and (3) assessment of induced sputum cell counts at the time of the SIC procedure. Forty‐nine (14.4%) subjects experienced dysphonia while exposed at their workplace. The baseline clinical features and sputum cell counts of the subjects with and without dysphonia as well as the univariate associations with dysphonia are detailed in Table 1. A multivariable logistic regression analysis was conducted in order to identify the clinical and inflammatory characteristics that were associated with work‐related dysphonia. The independent variables incorporated into these regression models included gender; sinusitis; high‐level treatment at work (i.e., Global Initiative for Asthma treatment step four‐fifths); poor asthma control at work (i.e., need for an inhaled short‐acting β2‐agonist once or more a day); OA caused by a low‐ versus a high‐molecular‐weight agent; as well as eosinophil and neutrophil sputum cell counts (expressed as % of total nonsquamous cells; Table 2).The multivariate logistic regression analysis revealed that female gender (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.06–3.92; p = 0.031) and a higher sputum neutrophil count (OR for each 5%‐increase in neutrophil count, 1.09; 95% CI, 1.01–1.18; p = 0.025) were significantly associated with a higher likelihood of work‐related dysphonia (Table 2). There was an association of borderline significance between dysphonia and high‐level treatment (OR, 1.97; 95% CI, 0.97–3.95; p = 0.057). Dysphonia showed a negative association with increased sputum eosinophil counts (OR, 0.41; 95% CI, 0.19– 0.83; p = 0.017). Dysphonia is a main symptom of worked‐associated irritable larynx syndrome (WILS) which has been defined as neuronal sensitization by a workplace trigger bringing about laryngeal dysfunction. As recently described, neutrophil inflammation can regulate sensory neuron function, especially in chronic pain. To our knowledge, our study is the first to describe a relationship between neutrophilic inflammation and work related dysphonia. We acknowledge the limitations inherent to the retrospective cross‐sectional design of this study. The presence of dysphonia was not objectively documented through direct visualization of inappropriate laryngeal movement. In addition, dysphonia was not assessed during the SIC procedure implying that it was not possible to ascertain that the agent inducing the positive SIC response was also the cause of dysphonia at work. Despite their inherent limitations, our findings suggest that airway neutrophilic inflammation could be involved in the development of work‐related laryngeal dysfunction. This study highlights the need for further prospective studies using validated questionnaires, laryngoscopy, and induced sputum analysis in order to explore the association between laryngeal dysfunction and neutrophilic airway inflammation.


Work-related dysphonia in subjects with occupational asthma is associated with neutrophilic airway inflammation
To the editor, Vertigan et al. 1 recently highlighted the comorbid association between asthma and laryngeal dysfunction, although the pathophysiological mechanisms underlying this complex association remain largely uncertain. 2 It is widely acknowledged that laryngeal dysfunction, including vocal cord dysfunction, can be triggered by external stimuli, such exercise, strong odors and irritant exposures. 2 In this regard, workplace exposure to respiratory irritants has been reported as an important cause of the "work-related irritable larynx syndrome". 3 We sought to assess the clinical characteristics and airway inflammatory processes associated with work-related dysphonia in a cohort of subjects with sensitizer-induced occupational asthma (OA) ascertained by a positive specific inhalation challenge (SIC). This retrospective study included 341 subjects identified among the multicenter European network for the PHenotyping of OCcupational ASthma (E-PHOCAS) 4 who met the following eligibility criteria: (1) complete information on variables addressing asthma severity and control while exposed at work; (2) available information on selfreported dysphonia (i.e. hoarseness or loss of voice) at work; and (3) assessment of induced sputum cell counts at the time of the SIC procedure.
Forty-nine (14.4%) subjects experienced dysphonia while exposed at their workplace. The baseline clinical features and sputum cell counts of the subjects with and without dysphonia as well as the univariate associations with dysphonia are detailed in Table 1. A multivariable logistic regression analysis was conducted in order to identify the clinical and inflammatory characteristics that were associated with work-related dysphonia. The independent variables incorporated into these regression models included gender; sinusitis; high-level treatment at work (i.e., Global Initiative for Asthma treatment step four-fifths); poor asthma control at work (i.e., need for an inhaled short-acting β 2 -agonist once or more a day); OA caused by a low-versus a high-molecular-weight agent; as well as eosinophil and neutrophil sputum cell counts (expressed as % of total nonsquamous cells; Table 2 Dysphonia is a main symptom of worked-associated irritable larynx syndrome (WILS) which has been defined as neuronal sensitization by a workplace trigger bringing about laryngeal dysfunction. 3 As recently described, neutrophil inflammation can regulate sensory neuron function, especially in chronic pain. 5 To our knowledge, our study is the first to describe a relationship between neutrophilic inflammation and work related dysphonia.
We acknowledge the limitations inherent to the retrospective cross-sectional design of this study. The presence of dysphonia was not objectively documented through direct visualization of inappropriate laryngeal movement. In addition, dysphonia was not assessed during the SIC procedure implying that it was not possible to ascertain that the agent inducing the positive SIC response was also the cause of dysphonia at work.
Despite their inherent limitations, our findings suggest that airway neutrophilic inflammation could be involved in the development of work-related laryngeal dysfunction. This study highlights the need for further prospective studies using validated questionnaires, laryngoscopy, and induced sputum analysis in order to explore the association between laryngeal dysfunction and neutrophilic airway inflammation.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Poor asthma control at work is defined as the use of SABA more than once a day. b High-level treatment defined according to GINA as treatment step 4 or 5. LETTER